Quinolone-induced arthropathy: exposure of magnesium-deficient aged rats or immature rats, mineral concentrations in target tissues and pharmacokinetics.
Quinolone treatment or magnesium deficiency induce identical cartilage lesions in juvenile rats and show additive arthropathogenic effects. It has been shown previously that neither condition is arthropathogenic in 8-week-old rats. Joint cartilage from aged individuals is rather prone to pathological alterations but information on prolonged quinolone treatment and/or dietarily induced magnesium deficiency in aged animals is not available. We treated magnesium-deficient (n = 9) aged Wistar rats (age 15 months) and age-matched controls with daily doses of 600 mg ofloxacin/kg body wt. by gastric intubation for 28 days. Further groups of magnesium-deficient and control rats (n = 9 and n = 10, respectively) received the vehicle only. Peak plasma concentrations of ofloxacin in adult rats were 20.5 +/- 5.6 mg/l (mean +/- SD) following treatment with a single dose of 600 mg/kg body wt. At the end of the experiment the degree of magnesium deficiency was most pronounced in plasma (Mg2+-def., 0.33 +/- 0.12 mmol/l; control, 0.97 +/- 0.08 mmol/l) and less pronounced in sternal cartilage (Mg2+-def., 10.8 +/- 3.6 mmol/kg dry wt; control, 13.3 +/- 2.8 mmol/kg dry wt), whereas the magnesium concentration in femoral bone remained unchanged (Mg2+-def., 201 +/- 13 mmol/kg dry wt; control, 204 +/- 11 mmol/kg dry wt). Histological investigation of the knee joints revealed no cartilage lesions following ofloxacin treatment, magnesium deficiency or a combination of both conditions. By contrast, cartilage lesions such as scars and erosions of the joint surface, chondrocyte clusters within acellular areas of the cartilage matrix and persisting clefts were detectable in knee joints from 7 of 10 adult rats (age 9 months) which had been treated with 4 x 600 mg fleroxacin/kg body wt. at 5 weeks of age. Mean plasma concentration of fleroxacin in juvenile rats was approx. 50 mg/l between 1.5 and 6 h after dosing and the drug was still detectable in plasma 48 h after dosing (0.4 +/- 0.1 mg/l). Our data indicate that joint cartilage in aged rats is not altered by a 4-week quinolone treatment, even during magnesium deficiency. Cartilage lesions in adult rats were only detectable if the animals had been treated during the sensitive phase at 5 weeks postnatally.
Förster
C
C
Institut für Klinische Pharmakologie und Toxikologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany.
Schwabe
R
R
Lozo
E
E
Zippel
U
U
Vormann
J
J
Günther
T
T
Merker
H J
HJ
Stahlmann
R
R
D000367:Age Factors; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000633:toxicity*; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002939:Ciprofloxacin / Q000097:blood / Q000633:toxicity; D000075202:Contraindications; D005260:Female; D016576:Fleroxacin / Q000097:blood / Q000633:toxicity*; D007592:Joint Diseases / Q000139:chemically induced* / Q000473:pathology; D007719:Knee Joint / Q000187:drug effects* / Q000473:pathology; D008274:Magnesium / Q000097:blood / Q000378:metabolism; D008275:Magnesium Deficiency / Q000097:blood / Q000473:pathology*; D008297:Male; D015242:Ofloxacin / Q000097:blood / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D000890:Anti-Infective Agents; D002939:Ciprofloxacin; D015242:Ofloxacin; D008274:Magnesium; D016576:Fleroxacin; D002118:Calcium